Efficacy of Bisphosphonate in Patients with Neurofibromatosis Type 1

Arzu Jalilova; Alessandra Cocca

doi:10.11005/jbm.24.809

jbm > Volume 32(1); 2025 > Article

Jalilova and Cocca: Efficacy of Bisphosphonate in Patients with Neurofibromatosis Type 1

Review Article

Journal of Bone Metabolism 2025;32(1):1-10.

Published online: February 28, 2025

DOI: https://doi.org/10.11005/jbm.24.809

Efficacy of Bisphosphonate in Patients with Neurofibromatosis Type 1

Arzu Jalilova¹

, Alessandra Cocca²

¹Department of Pediatric Endocrinology, Acıbadem İzmir Kent Hospital, İzmir, Türkiye

²Department of Pediatric Endocrinology, Evelina London Children’s Hospital, London, UK

Corresponding author: Arzu Jalilova, Department of Pediatric Endocrinology, Acıbadem İzmir Kent Hospital, Ataşehir, 8229/1 Sokak No. 56, 35620 Çiğli, İzmir, Türkiye,
Tel: +90-541-806-74-30, Fax: +90-0232-491-44-44, E-mail: dr_arzu@mail.ru

Received October 22, 2024 Revised January 20, 2025 Accepted January 20, 2025

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

This review aims to synthesize current knowledge regarding the use of bisphosphonates (BPs) in the treatment of bone complications in patients with neurofibromatosis type 1 (NF1). NF1 is a genetic disorder marked by multiple benign tumors of the nervous system and various skeletal abnormalities, such as osteoporosis and an increased risk of fractures. BPs are drugs that inhibit bone resorption, commonly used to treat osteoporosis and other bone diseases. The review identified multiple studies examining the effects of BP therapy in NF1 patients. Most studies reported improvements in bone mineral density and reduced fracture occurrence. The most commonly reported side effects were mild gastrointestinal symptoms and transient musculoskeletal pain. However, the evidence is limited by the small number of studies and the heterogeneity of patient populations and treatment protocols. In conclusion, BPs show improvements in managing NF1 complications such as osteoporosis and a reduction of fracture risk in NF1 patients. While the existing studies suggest positive outcomes, there is a need for more rigorous, large-scale studies to establish standardized treatment protocols and long-term safety profiles. Healthcare providers should consider BP therapy as a potential option for NF1 patients with significant bone complications, while also monitoring for possible adverse effects.

Key words: Bisphosphonates · Bone density · Neurofibromatosis 1 · Osteoporosis · Pseudarthrosis

GRAPHICAL ABSTRACT

INTRODUCTION

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder with an incidence of approximately 1 in 3,000 individuals worldwide.[1] NF1 is characterized by the presence of multiple neurofibromas, café-au-lait spots, and Lisch nodules. However, beyond these defining features, NF1 is also associated with various skeletal abnormalities, including scoliosis, pseudarthrosis, and osteoporosis. [2,3]

The pathophysiology of osteoporosis in NF1 patients is complex and not entirely understood, but it is believed to be related to the dysregulation of the Ras/mitogen-activated protein kinase pathway, which plays a crucial role in bone remodeling and homeostasis.[4]

Osteoporosis in NF1 patients is of particular concern due to the increased risk of fractures and the associated morbidity. Studies have shown that individuals with NF1 have reduced bone mineral density (BMD) compared to the general population, which contributes to their higher fracture risk.[5] The pathophysiology behind osteoporosis in NF1 is not fully understood, but it is believed to be multifactorial, involving genetic and hormonal influences.[6]

In addition to osteoporosis, congenital pseudoarthrosis of the tibia (CPT) is another notable osseous complication in NF1 patients. CPT is a rare and challenging condition characterized by anterolateral bowing of the tibia, which often progresses to spontaneous fracture and pseudarthrosis formation.[2] This condition can lead to significant morbidity, including limb length discrepancy and deformity.[7] The management of CPT is notoriously difficult, often requiring multiple surgical interventions, and healing is complicated by the pathological bone environment associated with NF1.[8]

Current management strategies for osteoporosis in NF1 patients primarily focus on lifestyle modifications and pharmacotherapy. Bisphosphonates (BPs), a class of drugs that inhibit bone resorption, are commonly used in the general population for the treatment of osteoporosis. They have been shown to increase BMD and reduce the incidence of fractures.[9,10] Given their efficacy in other populations, BPs are also being explored as a treatment option for osteoporosis in NF1 patients.

Despite the potential benefits, using BPs in NF1 patients requires careful consideration, as there are concerns about the long-term safety and efficacy of BP therapy in this unique patient population.[11]

Moreover, BPs have also been explored as a therapeutic option for managing skeletal manifestations such as CPT in NF1 patients. Studies suggest that BPs may help stabilize bone lesions and enhance healing processes in CPT. [12] However, further research is needed to better understand their efficacy and safety in this context.

This review aims to provide a comprehensive overview of the current knowledge regarding the use of BPs in NF1 patients with osteoporosis. By synthesizing findings from existing studies, we aim to highlight the potential benefits and challenges of this treatment approach, and to identify areas where further research is needed.

THE ROLE OF NEUROFIBROMIN IN BONE METABOLISM

Neurofibromin is a Ras guanosine triphosphatase-activating protein that negatively regulates the Ras signaling pathway. This regulation is crucial for maintaining cellular proliferation, differentiation, and survival. In bone, neurofibromin is expressed in osteoblasts, osteoclasts, and osteocytes, the key cells involved in bone formation and resorption.

1. Osteoblasts

Neurofibromin influences osteoblast differentiation and function. Osteoblasts are responsible for bone formation through the production of bone matrix and mineralization. The loss of neurofibromin leads to enhanced Ras/extracellular signal-regulated protein kinase (ERK) signaling, which has been shown to disrupt osteoblast differentiation and function, contributing to reduced bone formation and mineralization.[13]

2. Osteoclasts

These cells are involved in bone resorption. Dysregulated Ras signaling due to neurofibromin deficiency can also affect osteoclast activity. Studies suggest that increased osteoclast activity in NF1 patients leads to excessive bone resorption, contributing to bone fragility and osteoporosis. [14]

3. Osteocytes

As mechanosensors and regulators of bone remodeling, osteocytes function can be compromised by altered signaling pathways. Neurofibromin loss in osteocytes can disrupt their signaling and regulatory roles, further contributing to skeletal abnormalities in NF1.[15]

MECHANISMS OF SKELETAL ABNORMALITIES IN NF1

Several mechanisms have been proposed to explain the skeletal manifestations in NF1:

1. Enhanced ras/ERK signaling

The loss of neurofibromin results in hyperactive Ras/ERK signaling, which negatively affects osteoblast differentiation and function while promoting osteoclast activity. This imbalance leads to decreased bone formation and increased bone resorption, resulting in weaker bones prone to fractures and deformities.[14]

2. Impaired bone remodeling

Bone remodeling is a dynamic process involving the coordinated actions of osteoblasts and osteoclasts. In NF1, the impaired regulation of these cells disrupts the remodeling process, leading to the accumulation of defective bone tissue and structural abnormalities such as scoliosis and long bone dysplasia.[16]

3. Microarchitectural changes

Studies have shown that NF1 patients exhibit altered bone microarchitecture, including reduced trabecular thickness and connectivity, which contribute to overall bone weakness and susceptibility to fractures.[17]

4. Hormonal and metabolic influences

NF1 can also affect systemic factors that influence bone metabolism, such as hormonal regulation and metabolic status. For example, abnormalities in growth hormone and vitamin D metabolism have been observed in NF1 patients, which can further exacerbate bone metabolic defects.[18]

VITAMIN D RECEPTOR (VDR) EXPRESSION

Studies have consistently demonstrated a reduced expression of the VDR in patients with NF1, which could diminish the efficacy of vitamin D supplementation in improving BMD and bone mineral content.[19,20]

Notably, immunohistochemical analyses have revealed that VDR expression is frequently absent or significantly reduced in NF1-associated tumors. This suggests a potential mechanism that impairs vitamin D’ s beneficial role in bone health for NF1 patients.[20]

These findings emphasize the need for further investigation to understand how VDR expression influences the pathophysiology of NF1 and its implications for bone health management.

BONE TURNOVER AND NF1-RELATED OSTEOPOROSIS

Bone turnover markers such as serum C-terminal telopeptide (CTX) and procollagen type N-terminal propeptide of type I collagen (P1NP) play a critical role in understanding bone metabolism in NF1 patients. Serum CTX is a marker of bone resorption, while P1NP reflects bone formation. These markers are often coupled, with increased bone resorption (indicated by elevated CTX levels) typically followed by increased bone formation (reflected in P1NP levels). However, the CTX/P1NP ratio provides insight into the net bone balance, with a higher ratio indicating a predominant bone catabolic state.[11]

Studies have shown that NF1 patients exhibit elevated levels of both CTX and P1NP compared to controls, with an increased CTX/P1NP ratio.[21] This suggests an enhanced bone turnover rate skewed toward catabolism, leading to net bone loss. While these findings underline the utility of CTX and P1NP in evaluating bone health in NF1, it is important to recognize the limitations of these markers. For instance, they do not directly measure bone density or structural integrity, which are crucial in assessing fracture risk. Nonetheless, their ability to reflect dynamic changes in bone metabolism makes them valuable in monitoring disease progression and potential therapeutic responses in NF1-related osteoporosis.

OSTEOPOROSIS IN NF1 PATIENTS

Generalized osteopenia is a common skeletal complication observed in patients with NF1.[22,23] This condition is characterized by reduced BMD and increased bone fragility, predisposing patients to fractures even with minimal trauma. Several studies have investigated the prevalence, pathophysiology, and management of osteoporosis in NF1 patients, highlighting the unique challenges faced by this population.

Lodish et al. [24] found that children and young adults with NF1 had significantly lower BMD, which could predispose them to fractures.

A Finnish study involving 460 NF1 patients and 3,988 controls reported an increased age-dependent fracture risk among NF1 patients. Specifically, older adults (41+ years) had a risk ratio of 5.2 and children had a ratio of 3.4, compared to controls. These findings suggested the need for prophylactic measures to prevent fractures in NF1 patients.[25]

Filopanti et al. [22] found alterations in the trabecular bone score, a measure of bone microarchitecture. This suggests that bone quality, in addition to bone density, is compromised in NF1.

In a study involving 57 NF1 patients, 75.44% exhibited bone abnormalities (syndactyly, pseudarthrosis, patellar dislocation, macrocephaly, short stature, scoliosis). Among these, scoliosis was the most common, occurring in 59.65% of the patients. Specific markers indicated that bone resorption predominates over bone formation, significantly decreasing BMD and predisposing NF1 patients to premature bone mass loss.[26]

As shown in Table 1, the International Society for Clinical Densitometry (ISCD) guidelines provide a comprehensive framework for diagnosing pediatric osteoporosis.[27] These criteria are particularly relevant in the context of NF1, where patients may be at increased risk of low bone density and fractures.

In the context of NF1, recognizing these criteria is essential for early identification and management of osteoporosis, as patients with NF1 may be at increased risk for low bone density and fractures.

In their study, Stevenson et al. [5] investigated bone density among children and adolescents with NF1, identifying a notable incidence of low BMD. After having assessed a cohort of NF1 patients, the researchers observed that approximately 45% had BMD Z-scores below −1.0, indicating lower bone density. This investigation highlighted the multifaceted impact of genetic and endocrine factors on bone health within the NF1 population, suggesting a need for a comprehensive approach that considers the complex interactions between these factors, particularly the role of genetic modifiers, in managing bone density and skeletal defects.[5]

In a study where progressive bone density loss was observed in NF1 patients over time, researchers emphasized the necessity of regular monitoring and early intervention for managing bone health in this population.[28]

Elefteriou et al. [4] compiled data from multiple case studies, which consistently highlighted reduced BMD and increased fracture risk among various populations of NF1 patients. The review also underlined the impact of earlyonset osteoporosis in younger individuals with NF1.

In a study conducted by Brunetti-Pierri and collegues [19], significant reductions in BMD and overall bone mass were observed in NF1 patients. Following supplementation with calcium and vitamin D, normalization of parathyroid hormone levels occurred; however, there was no significant improvement in BMD and bone mineral content over a two-year follow-up period. The study also suggests the need for prospective clinical trials to evaluate whether more aggressive interventions, such as BPs, could increase bone mass in young adults with NF1.[19]

TREATMENT

Managing fractures in patients with NF1 necessitates a multifaceted approach that comprehensively addresses all determinants of bone health. It is imperative to identify and mitigate risk factors that compromise bone density and mass.

Effective management of osteoporosis and fractures in NF1 patients relies on comprehensive diagnostic evaluations. Laboratory tests and imaging methods provide critical insights into bone health, guide treatment decisions, and monitor therapy effectiveness (Table 2, 3).

Initial therapeutic strategies should focus on safe and effective interventions.

Physical activity is a critical component in enhancing BMD, offering benefits both to NF1 patients and the general population (Table 4). Ensuring adequate calcium intake, tailored to specific age requirements, is imperative, alongside maintaining optimal vitamin D levels through appropriate supplementation.

In the realm of pharmacological treatments, BPs are extensively employed to manage conditions such as osteogenesis imperfecta and secondary pediatric osteoporosis. These agents are particularly indicated for pediatric patients with a history of fractures not attributable to significant trauma. Intravenous BPs, including pamidronate, neridronate, and zoledronate, are commonly administered and constitute the first-line treatment for augmenting BMD in patients with NF1. The utilization of these pharmacotherapies is supported by evidence demonstrating their efficacy in increasing bone density and reducing fracture rates in this population.[29-31]

1. Pamidronate

Intravenous pamidronate is one of the most widely used BPs for the treatment of pediatric osteoporosis and conditions like NF1, despite limited robust evidence regarding optimal dosage, therapy duration, and long-term safety. Typical dosing regimens for pamidronate involve administering 0.5 to 1 mg/kg/day for three consecutive days every three months. A study involving nine pediatric and adolescent patients (aged 10.1-17.4 years) with secondary osteoporosis, including two with NF1, showed significant pain relief and increased BMD Z-scores in the lumbar spine and femoral neck. However, some patients developed fever and symptomatic hypocalcemia after the first treatment cycle.[29]

2. Risedronate

In a case study on the use of risedronate for treating osteoporosis associated with NF1, a 19-year-old patient with severe low bone mass due to NF1 underwent a one-year regimen of 35 mg risedronate sodium weekly, combined with daily intake of 1,200 mg calcium and 800 IU vitamin D. The treatment resulted in significant improvements, with Z-scores and BMD increasing by 24.4% at the lumbar site and 15.0% at the hip, with no adverse effects reported. [30]

3. Alendronate

A prospective study examining the effects of oral alendronate treatment (70 mg) on individuals with NF1-related osteoporosis reported that, after 23 months of treatment, lumbar spine BMD increased by an average of 2.4% from a baseline of 0.869 g/cm², and femoral neck BMD increased by 0.8% from a baseline of 0.696 g/cm². However, these differences were not statistically significant. Additionally, reductions in bone turnover markers suggested decelerated bone remodeling, highlighting the need for larger-scale trials to comprehensively evaluate the efficacy of BPs in managing NF1-related osteoporosis.[32]

4. Zoledronic acid (ZA)

In a study involving 27 patients with secondary osteoporosis, including one patient with osteoporosis due to NF1, treatment with ZA at a dose of 0.05 mg/kg every 6 months for 12 months resulted in increased BMD, reduced bone turnover, and improved vertebral morphology. The median age at ZA start was 10.5 years (range, 6.2-13.3), indicating that the study was conducted in the childhood period. Following the first infusion, some patients experienced acute phase reactions such as asymptomatic hypocalcemia, fever, pain, and nausea. However, no fractures were observed during the treatment period, and the growth parameters of the treated patients remained normal. These findings indicate that ZA can be used in treating secondary osteoporosis in children with good outcomes.[31]

A separate study involving 20 NF1 patients indicated elevated serum bone turnover markers (CTX and P1NP) and found that 15 out of 20 had low BMD, despite the absence of typical risk factors. BPs, including ZA, showed limited efficacy in reducing osteoclast numbers in NF1 patients in vitro, potentially due to Ras pathway dysregulation.[21]

ZA and other BPs have demonstrated effectiveness in preserving bone density and reducing bone turnover in pediatric patients with secondary osteoporosis and NF1-related bone conditions. Despite their efficacy, certain cases, particularly those involving complex bone healing challenges such as CPT in NF1 patients, may benefit from adjunct therapies.

In such cases, recombinant bone morphogenetic proteins (BMPs) have emerged as a valuable addition to BP treatment. BMPs, specifically BMP-2 and BMP-7, are critical in promoting bone formation and healing.

However, when BMP-2 therapy is combined with BPs like ZA, the bone regeneration effects are significantly enhanced. ZA inhibits bone resorption, allowing the BMP-2 to work more effectively in stimulating new bone formation. In a specific study involving NF1-deficient mice, the combined use of BMP-2 and ZA led to a marked improvement in bone healing compared to BMP-2 therapy alone, suggesting that BPs can play a crucial role in enhancing BMP-mediated bone repair in NF1-related conditions. This combination therapy highlights the therapeutic benefit of using BPs alongside BMPs in treating NF1-related orthopedic complications.[33]

In a study, six cases of CPT associated with NF1 were treated with BMP7 during surgery, followed by BPs (pamidronate and/or ZA) treatment 2 to 3 weeks later. Initial doses were 0.5 to 1.0 mg/kg for pamidronate or 0.0125 mg/kg for zolendronic acid, followed by pamidronate 1.0 to 1.5 mg/kg or ZA 0.025 to 0.05 mg/kg at 6 to 8 weeks and every 3 to 6 months thereafter. Patients received a median of two bisphoshonate doses (range, 1-6) postoperatively. In this study, six out of eight cases showed healing within an average of 5.5 months. It is suggested that the combination of BMP and BPs may preserve bone formation by inhibiting osteoclastic bone loss.[12]

Schindeler et al. [34] examined the role of BPs in the treatment of CPT associated with NF1. The study demonstrated that the combination of ZA with recombinant human BMP-2 (rhBMP-2) enhanced bone healing post-surgery by boosting anabolic stimulation in NF1-deficient mice. In mice treated with rhBMP-2, fractures showed a 75% non-union rate within three weeks, which decreased to 37.5% with the addition of ZA. These findings suggest that BPs, by preventing bone loss and supporting anabolic stimulation, may improve surgical outcomes for children with congenital pseudarthrosis of the tibia and NF1.[34]

In an NF1-associated tibial pseudarthrosis murine model, treatment with rhBMP-2 significantly improved bone healing (87% union), while combining rhBMP-2 with ZA further increased bone volume and mechanical strength (93% union). This combination also reduced fibrous tissue infiltration at the fracture site, promising future clinical use in NF1 pseudarthrosis management.[35]

In the case of NF1-associated dystrophic scoliosis, lumbar fusion revision with intraoperative rhBMP-2 was performed. Following the detection of a left posterior iliac periscrew fracture, the patient received 5 mg of intravenous ZA at 3 months post-surgery to inhibit bone resorption, and asfotase alfa (2 mg/kg, three times per week for 6 months) starting at 7 months. This treatment regimen resulted in stable spinal fusion and healing of the iliac screw fracture after 14 months.[36]

The following section provides a concise summary of the treatment strategies discussed above, highlighting key interventions, dosages, and observed outcomes in NF1-related osteoporosis and fracture management.

TREATMENT OVERVIEW

To summarize, the treatment of NF1-related osteoporosis and fractures involves a combination of pharmacological and non-pharmacological strategies. Key treatment options include:

1. Physical activity

Essential for enhancing BMD and overall bone health.

Calcium and Vitamin D Supplementation: Adequate intake is crucial for bone health, tailored to age-specific requirements.

2. Pharmacological treatments

Pamidronate (Intravenous): 0.5-1 mg/kg/day for 3 consecutive days every 3 months.

Risedronate (Oral): 35 mg weekly, combined with daily calcium (1,200 mg) and vitamin D (800 IU).

Alendronate (Oral): 70 mg weekly.

ZA (Intravenous): 0.05 mg/kg every 6 months for 12 months.

3. Follow-up period

Monitoring of BMD should be performed at regular intervals, typically every 6 to 12 months, depending on patient response and treatment protocol.

EFFICACY AND SAFETY

The efficacy and safety of BPs in NF1 patients have been evaluated in several studies, although the number of participants is generally small, and the study designs are heterogeneous.

1. BMD

Most studies report improvements in BMD following BP therapy. The increases in BMD are generally observed in the lumbar spine and femoral neck, the sites most commonly measured. These improvements suggest that BPs can enhance bone strength and potentially reduce fracture risk in NF1 patients.[28,31]

2. Fracture risk

There is limited direct evidence on the impact of BPs on fracture risk in NF1 patients. However, the observed increases in BMD imply that BP therapy may contribute to a reduction in fracture risk. More research is needed to directly assess this outcome.

3. Side effects

The most common side effects reported with BP therapy include mild gastrointestinal symptoms, transient musculoskeletal pain, and acute-phase reactions such as fever and flu-like symptoms, particularly with intravenous formulations like ZA. Hypocalcemia is another potential side effect, highlighting the importance of monitoring calcium and vitamin D levels during treatment.[28,31]

4. Long-term safety

The long-term safety of BP therapy in NF1 patients is not well-established. Concerns include the potential for atypical femoral fractures and osteonecrosis of the jaw with prolonged use. Therefore, the duration of therapy and the risk-benefit ratio should be carefully considered on an individual basis.[11]

In the context of NF1, where bone abnormalities such as osteoporosis and an increased risk of fractures are prevalent, BPs may offer therapeutic benefits. However, the decision to initiate BP therapy should be individualized, taking into account the severity of bone involvement, the presence of symptoms, and the potential risks associated with treatment. Further research is needed to establish definitive guidelines for the use of BPs in pediatric NF1 patients.

In summary, while BPs can be effective in increasing BMD and potentially reduce fracture risk in children, including those with NF1, careful consideration of the safety profile and close monitoring during treatment are essential.

CONCLUSIONS

Osteoporosis is a significant and common complication in NF1 patients, driven by genetic mutations, hormonal imbalances, and disrupted cellular mechanisms. Regular monitoring of bone density and early interventions are crucial in managing and mitigating the impact of osteoporosis in these individuals. Future research should focus on understanding the precise molecular pathways involved and developing targeted therapies to improve bone health in NF1 patients.

DECLARATIONS

Funding

The authors received no financial support for this article.

Ethics approval and consent to participate

Not applicable.

Conflict of interest

No potential conflict of interest relevant to this article was reported.

Table 1

International Society for Clinical Densitometry criteria for diagnosing pediatric osteoporosis

Criteria	Details
Vertebral compression fractures	One or more vertebral compression fractures not resulting from high-impact trauma or localized pathology
BMD Z-score and fracture history	A BMD Z-score of −2.0 or lower, along with a significant fracture history, characterized by: - Two or more long bone fractures by age 10, or - Three or more long bone fractures at any age up to 19 years

BMD, bone mineral density.

Table 2

Laboratory tests

Laboratory test	Purpose
Calcium levels	Assess calcium deficiency risk, often present in NF1 patients
Phosphate levels	Regulation of bone mineralization and metabolism
Vitamin D deficiency	Impact of low vitamin D levels on bone health
Alkaline phosphatase levels	Indicator of increased bone turnover and remodeling
PTH levels	Effect on calcium metabolism and bone health
Creatinine levels	Assessment of kidney function prior to the use of bisphoshonates
CTX	Measure bone resorption (osteoclast activity), often elevated in NF1 patients
P1NP	Indicator of bone formation, useful in assessing bone turnover

NF1, neurofibromatosis type 1; PTH, parathyroid hormone; CTX, C-terminal telopeptide; P1NP, procollagen type N-terminal propeptide of type I collagen.

Table 3

Imaging methods

Imaging method	Purpose	Relevance in NF1
X-ray	Initial screening for bone fractures and abnormalities	Identify fractures and significant bone deformities
DXA	- Bone mineral density measurement - Vertebral fractures assessment	- Diagnose osteopenia or osteoporosis - Identify vertebral fractures
QCT	Quantitative assessment of bone mineral density and strength	Provide detailed insights into bone microarchitecture
CT	Detailed imaging for fracture diagnosis and localization	Offer comprehensive views of complex bone structures and injuries

NF1, neurofibromatosis type 1; DXA, dual energy X-ray absorptiometry; QCT, quantitative computed tomography; CT, computed tomography.

Table 4

Lifestyle modifications for bone health

Lifesyle modification	Details
Calcium intake	For children - Ensure adequate daily calcium intake to support bone health - Recommended daily intake varies by age: - Birth-6 months: 200 mg/day - 6-12 months: 260 mg/day - Over 12 months: >500 mg/day [37] For adult - Recommended daily intake: 1,000-1,200 mg/day
Vitamin D supplementation	For children - Prophylaxis: 400-1,000 IU/day, depending on age and baseline vitamin D status - Treatment of secondary osteoporosis: 1,000-2,000 IU/day, monitored by healthcare provider [37] For adult - Supplement with vitamin D to maintain optimal levels for bone health - Recommended daily intake: 800-1,000 IU/day - Sun exposure and dietary sources (fatty fish, fortified foods) may also contribute - Monitor serum levels periodically
Physical activities	- Engage in weight-bearing exercises (walking, jogging, dancing) to strengthen bones and improve balance - Include resistance training to enhance bone density [38] - Consult with a physical therapist for a personalized exercise program - Avoid high-impact activities that may increase fracture risk

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